Characterisation and optimisation of amorphous suspensions

Abstract

Suspensions with amorphous drug in aqueous media are emerging as one of the promising formulation options to increase the in vivo exposure of the drug in preclinical toxicology studies involving poorly water soluble drugs. These formulations should be physically stable during the course of the study, which is typically several weeks. However, the aqueous environment and the inherent unstable nature of the amorphous form make crystallisation almost inevitable. The crystallisation can occur either during storage of the amorphous form in aqueous suspensions or during dissolution in the gastrointestinal tract. Hence, the characterisation of crystallisation behaviour and development of strategies to prevent crystallisation in amorphous suspensions at those two stages were the aims of this thesis. Poorly soluble indomethacin (IND) was selected as model drug for the studies. Firstly, the crystallisation behaviour of amorphous IND in aqueous suspension during storage was investigated at different pH values and temperatures (without excipients). The crystallisation onset time (detected by FTIR spectroscopy) decreased with decreasing temperature, but not pH. However, this decrease was not significant enough for temperature to be used as a method for crystallisation inhibition. This indicated that excipients, such as polymers, must be used to improve the physical stability. Interestingly, diverse polymorphic forms were observed, with three new forms being identified; these were named ε, ζ and η form. A This led to the additional conclusion that amorphous suspensions are worth considering when performing polymorphic screening studies. In a subsequent study, the potential of different polymers (poly(vinyl pyrrolidone) (PVP), hydroxypropyl methyl cellulose (HPMC) and Soluplus® (SP)) and polymer addition methods (solid dispersion (SD) with IND or predissolved polymer solution) to inhibit IND crystallisation and maintain supersaturation of amorphous IND, during storage in the aqueous suspensions was investigated. The SDs were better at inhibiting IND crystallisation than the predissolved polymer solution. SDs were also better at maintaining the supersaturations generated upon dissolution of amorphous IND. Use of SP showed more IND crystallisation inhibition and supersaturation potential than the other polymers. However, this depended on the method of addition. The IND in SD with the SP did not crystallise or generate any supersaturation, whereas IND in the corresponding predissolved solution crystallised into the new η form but also led to a more than 20-fold higher IND solution concentration than was observed for the crystalline IND. The ranking of the SDs with respect to crystallisation inhibition potential was SP SD >>> PVP SD > HPMC SD. This shows that the crystallisation inhibition depends strongly on the type of polymer used. Therefore, mechanisms behind the polymer actions were investigated in relation to the antiplasticisation ability of the polymers and nature and strength of the drug–polymer interactions. The stability of the IND–polymer systems was not correlated to Tg, but was rather the strength of drug–polymer interactions predicted by various methods. The IND–SP dispersion had the strongest drug polymer interactions and was the most stable SD followed by the SD with PVP and then HPMC. Hence, this work suggested it is more important to consider the role and the relative strengths of drug–polymer interactions than the Tg, when selecting a polymer to inhibit crystallisation in aqueous suspensions of amorphous SD with different polymers. The effect of polymer and polymer addition method on crystallisation and dissolution was also investigated during dissolution testing using pH 5.5 and 6.8 buffers. At pH 5.5, in contrast to the suspensions of pure amorphous form with and without predissolved polymer, freshly–prepared suspensions with the SDs did not crystallise during dissolution and hence showed increased IND dissolution. Again, presumably due to the stronger drug–polymer interactions, IND dissolved more slowly from the freshly–prepared SD with SP than those with PVP or HPMC. In stored samples, the IND from PVP and HPMC SDs had crystallised in the suspensions, resulting in a marked decrease in the dissolution as compared to that from freshly prepared suspensions. In contrast, the dissolution profile of the physically stable suspensions of IND SD with SP remained unchanged and importantly was better than that obtained with the stored suspensions of PVP and HPMC SDs. SP SD, when subjected to dissolution testing at pH 6.8, showed a marked increase in the dissolution rate as compared to that observed at pH 5.5. This indicated that amorphous suspensions, with SDs and SP can fulfill the stability and dissolution requirements to increase the in vivo exposure of the drug. Overall, the work in this thesis showed that, aqueous amorphous suspensions can be systematically characterised and optimised. Sufficiently stable amorphous suspensions during storage for several weeks and dissolution were obtained. Moreover, from the findings of the thesis, short-cut steps can be recommended for selecting suitable polymers and methods of addition for amorphous suspension development in future. This will be especially useful in various areas for drug delivery, including not only toxicology studies, but also potentially paediatric and veterinary formulations, where long term physical stability of amorphous form in the aqueous suspension is required.